rs797044702

Positions:

• chrX-101401710-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000169.3(GLA):​c.469C>T​(p.Gln157Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA NM_000169.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 0.470

Genes affected

GLA (HGNC:4296): (galactosidase alpha) This gene encodes a homodimeric glycoprotein that hydrolyses the terminal alpha-galactosyl moieties from glycolipids and glycoproteins. This enzyme predominantly hydrolyzes ceramide trihexoside, and it can catalyze the hydrolysis of melibiose into galactose and glucose. A variety of mutations in this gene affect the synthesis, processing, and stability of this enzyme, which causes Fabry disease, a rare lysosomal storage disorder that results from a failure to catabolize alpha-D-galactosyl glycolipid moieties. [provided by RefSeq, Jul 2008]

RPL36A-HNRNPH2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-101401710-G-A is Pathogenic according to our data. Variant chrX-101401710-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 196225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101401710-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLA	NM_000169.3	c.469C>T	p.Gln157Ter	stop_gained	3/7	ENST00000218516.4	NP_000160.1
RPL36A-HNRNPH2	NM_001199973.2	c.300+6253G>A		intron_variant			NP_001186902.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.469C>T	p.Gln157Ter	stop_gained	3/7	1	NM_000169.3	ENSP00000218516	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 29, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 21, 2017	The Q157X pathogenic variant in the GLA gene has been reported in multiple individuals with Fabry disease (Eng et al., 1994; Shabbeer et al., 2005; Schafer et al., 2005; Johnson et al., 2013). In addition, Q157X has been classified as a pathogenic variant by another clinical laboratory in ClinVar (SCV000228801.1; Landrum et al., 2016). Q157X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Functional studies show the Q157X pathogenic variant results in increased levels of lyso-globotriaosylsphingosine, a biomarker for Fabry disease (Lukas et al., 2013). Other nonsense variants in the GLA gene have been reported in HGMD in association with Fabry disease (Stenson et al., 2014). Furthermore, the Q157X pathogenic variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, Q157X in the GLA gene is interpreted as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 16, 2019	- -

Fabry disease Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jul 09, 2023	The c.469C>T (p.Gln157*) variant of the GLA gene is located in exon 3 and is predicted to cause loss of normal protein function either through abnormal, prematurely truncated protein, or by absence of protein product due to nonsense-mediated mRNA decay. The loss-of-function variants in GLA gene are known to be pathogenic for Fabry disease (PMID: 10666480, 12175777). This variant has been identified in individuals with Fabry disease (PMID: 7531540, 16595074, 18849176). This variant has not been identified in the general population according to gnomAD. For these reasons, the c.469C>T (p.Gln157*) variant in the GLA gene has been classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 02, 2023	For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Gln157*) in the GLA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GLA are known to be pathogenic (PMID: 10666480, 12175777). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Fabry disease (PMID: 7531540, 16595074, 18849176, 23935525). ClinVar contains an entry for this variant (Variation ID: 196225). -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 29, 2022

The p.Q157* pathogenic mutation (also known as c.469C>T), located in coding exon 3 of the GLA gene, results from a C to T substitution at nucleotide position 469. This changes the amino acid from a glutamine to a stop codon within coding exon 3. This variant has been detected in several individuals reported to have Fabry disease (FD) or features consistent with FD, including reported de novo occurrences (Eng CM et al. Hum Mol Genet, 1994 Oct;3:1795-9; Eng CM et al. Mol Med, 1997 Mar;3:174-82; Schäfer E et al. Hum Mutat, 2005 Apr;25:412; Shabbeer J et al. Hum Genomics, 2006 Mar;2:297-309; Erdos M et al. Mol Genet Metab, 2008 Dec;95:224-8; Johnson B et al. Ann Lab Med, 2013 Jul;33:274-8; Lukas J et al. PLoS Genet, 2013 Aug;9:e1003632; Jain R et al. JACC Cardiovasc Imaging, 2018 Apr;11:644-647). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	30
DANN	Uncertain	0.98
FATHMM_MKL	Benign	0.37	N
MutationTaster	Benign	1.0	A
Vest4		0.91
GERP RS		-5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs797044702; hg19: chrX-100656698;